Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgement and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is the leading cause of dementia in the elderly, today affecting 4-5 million Americans, which is expected to increase to 8-10 million Americans within the next 25 years. Currently there is no effective therapeutic treatment for AD, and there is lack of a definitive biochemical test to identify AD patients and/or to monitor their progression. Perlecan, a specific heparan sulfate proteoglycan (PG), accumulates in the beta-amyloid (Abeta) deposits and neurofibrillary tangles (NFTs) of AD and is postulated to play important roles in AD pathogenesis. Our preliminary data indicates that we have identified two splice variants of perlecan which are present in the brains of most patients with AD, and which specifically immunolocalize to either amyloid plaques or NFTs. Our initial studies also suggest that the specific splicing of perlecan may be important for amyloid and NFT formation in AD. The overall objective of this phase I SBIR proposal is to determine whether these two identified perlecan splice variants are specific for AD, and to assess their potential roles in amyloid plaque and NFT pathogenesis. In addition, use of perlecan splice variant specific antibodies will determine whether these perlecan splice variants are present in biological fluids (i.e. blood, cerebrospinal fluid) and may potentially serve as new diagnostic markers for AD and its progression. The studies described in this phase I SBIR proposal are therefore believed to have both therapeutic and diagnostic implications. In a future phase II proposal, it is anticipated that studies will be implemented to design potential anti-amyloid plaque and/or NFT therapeutics based on the knowledge acquired from Phase I. In addition, if a particular perlecan splice variant appears to be a potential biochemical marker for AD as determined in phase I, it will be further assessed in a larger study to confirm if a new diagnostic indicator for AD and/or its progression has been found. PROPOSED COMMERCIAL APPLICATIONS: Alzheimer's disease (AD) currently affects 4-5 million Americans at an estimated cost of $80-$l00 billion. Currently, there is no cure or effective treatment and the patient usually dies from 3-10 years from disease onset. Additionally, there is no reliable biochemical test or indicator for AD and its progression. It is estimated that the current world-wide market for a effective AD therapeutic is $24 billion, whereas the world-wide market for a specific biochemical marker to monitor AD and its progression is $15 billion. Potential licensing opportunities for the development of new therapeutics and/or diagnostics for AD are also anticipated to yield substantial revenues in the future.